US2025011303A1PendingUtilityA1
Small molecule modulators of il-17a, methods of making and methods of using thereof
Est. expiryMay 18, 2043(~16.8 yrs left)· nominal 20-yr term from priority
C07D 493/10C07D 403/12C07D 491/052C07D 498/10A61K 31/5386A61K 31/4155C07D 491/20A61P 29/00A61P 37/00A61K 31/397C07D 495/20C07D 405/14A61K 31/4725A61K 31/538C07D 405/12C07D 409/14C07D 413/14C07D 471/04C07D 491/10C07D 405/06C07D 495/10C07D 403/14C07D 401/14C07D 401/12C07D 471/10C07D 491/107
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Claims
Abstract
The present application describes compounds of IL-17A modulator that are useful for treating an IL-17A mediated inflammatory syndrome, disorder, or disease.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof,
wherein Ring C is aryl, 5-6 membered heteroaryl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, R x —C 3-10 cycloalkyl, R x —C 3-10 heterocyclyl, R x -aryl and R x -5-6 membered heteroaryl; wherein R x is halo or —C 1-6 alkyl;
wherein Ring C is optionally substituted with one or more R 1 ;
wherein each R 1 is independently selected from the group consisting of OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CO—C 1-6 alkyl, —CO—C 1-6 haloalkyl, —CO—NR 3a R 3b , C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
wherein each R 1 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, oxo, —OH, —CN, —C 1-6 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkoxy, —C 1-6 haloalkyl, —C 3-10 cycloalkyl, heterocyclyl, —C 6-10 aryl, 5-10 membered heteroaryl, —S(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl and —S—C 1-6 alkyl;
wherein n is 0 or 1;
wherein R 2 is selected from the group consisting of —C 0-1 alkyl-C 3-9 cycloalkyl, —C 1-6 alkyl and —C 1-2 alkyl-O—C 1-3 alkyl, wherein the —C 0-1 alkyl-C 3-9 cycloalkyl, the —C 1-6 alkyl or the —C 1-2 alkyl-O—C 1-3 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of C 3-6 cycloalkyl, halo, CH 3 , CHF 2 , CF 3 , OH and oxo;
wherein X 1 is NH, O, or S;
wherein X 2 is N, O, or S; and wherein X 2 is optionally attached to an atom in Ring A and forms another ring next to Ring A;
wherein X 3 is O or —CR c R d ; and wherein each of R c and R d is independently selected from the group consisting of H, halo and —C 1-6 alkyl;
wherein Ring A is selected from the group consisting of
wherein each of Z 1 , Z 2 and Z 3 is independently selected from the group consisting of —N═, —N(═O)═ and —C(R a )═, wherein R a is selected from the group consisting of H, F, Cl, Br, I, —C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OH, CN, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, aryl and 5-10 membered heteroaryl;
wherein Ring B, which is fused to Ring A, is selected from the group consisting of 4-7 membered heterocycloalkyl, 4-7 membered heterocycloaryl, 4-7 membered cycloalkyl, and 4-7 membered cycloalkenyl, wherein each of the 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloaryl, the 4-7 membered cycloalkyl, and the 4-7 membered cycloalkenyl is optionally saturated or unsaturated bridged-ring;
wherein Ring B is optionally substituted with one or more R b , each of R b is independently selected from the group consisting of CN, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CO—C 1-6 alkyl, COOC 1-6 alkyl, —CO—C 1-6 haloalkyl, —CO—NR 3a R 3b , —CH 2 —NR 3a R 3b , —NR 3a —CO—C 1-6 alkyl, —NR 3a —COOC 1-6 alkyl, —NR 3a —CO—C 1-6 haloalkyl, —NR 3a —CO—NR 3a R 3b , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-6 alkyl —C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl, —C 1-6 alkyl —C 6-10 aryl, —C 1-6 alkyl-5-10 membered heteroaryl, F, —CH 3 , —CHF 2 , —CF 3 , and OH; wherein two R b groups are optionally combined to form a C 3-10 cycloalkyl or a heterocyclyl or a C 6-10 aryl or 5-10 membered heteroaryl; wherein each R b is optionally substituted with one or more substituents each independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CO—C 1-6 alkyl, COOC 1-6 alkyl, —CO—C 1-6 haloalkyl, —CO—NR 3a R 3b , —CH 2 —NR 3a R 3b , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
wherein Ring B is substituted with R 3 , wherein R 3 is selected from the group consisting of —CONR 3a R 3b , —S(O)—NR 3 R 3b , —S(O) 2 —NR 3a R 3b , —C 0-6 alkyl-CONR 3a R 3b , —C 0-6 alkyl-NR 3a R 3b , —N(R 3a )—COR 3a , —N(R 3a )—CONR 3a R 3b , —C 0-6 alkyl-SONR 3a R 3b , —C 0-6 alkyl-SO 2 NR 3a R 3b , —C(S)—NR 3a R 3b , CN, 5-10 membered heteroaryl, —COR 3a , —P(O)(OR 3a )(OR 3b ), —S(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, C 1-6 alkyl, —C 1-6 alkyl-C 3-10 cycloalkyl, —O—C 1-6 alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl and alkylcycloalkyl; wherein the 5-10 membered heteroaryl, the —S(O)—C 1-6 alkyl, the —S(O) 2 —C 1-6 alkyl, the C 1-6 alkyl, the —C 1-6 alkyl-C 3-10 cycloalkyl, the —O—C 1-6 alkyl, the aryl, the heterocyclyl, the alkylheterocyclyl, the alkylaryl or the alkylcycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl;
wherein each of R 3a and R 3b is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C 0-2 alkyl-C 3-6 cycloalkyl, and 5-6 membered heterocyclyl; or R 3a and R 3b are optionally combined to form a C 3-10 cycloalkyl, a heterocyclyl, a C 6-10 aryl, or a 5-10 membered heteroaryl; wherein the C 1-6 alkyl, the C 1-6 haloalkyl, the —C 2-6 alkenyl, the —C 2-6 alkynyl, the C 0-2 alkyl-C 3-6 cycloalkyl, the 5-6 membered heterocyclyl, the C 3-10 cycloalkyl, the heterocyclyl, the C 6-10 aryl, or the 5-10 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 haloalkyl.
2 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Ring B is fused to Ring A and selected from the group consisting of:
wherein each of R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 is independently selected from the group consisting of —C 1-6 alkyl, —C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CO—C 1-6 alkyl, COOC 1-6 alkyl, —CO—C 1-6 haloalkyl, —CO—NR 3a R 3b , —CH 2 —NR 3a R 3b —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl, —C 1-6 alkyl-C 6-10 aryl, —C 1-6 alkyl-5-10 membered heteroaryl, H, F, —CH 3 , —CHF 2 , —CF 3 , and OH; and wherein any two of R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 and R 3 are optionally combined to form a C 3-10 cycloalkyl or a heterocyclyl or a C 6-10 aryl or 5-10 membered heteroaryl; wherein each of X b1 and X b2 is independently C, N, O or S.
3 . The compound of claim 2 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein each of R b1 and R b2 is independently selected from the group consisting of:
4 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the R 3 group is selected from the group consisting of: —CONR 3a R 3b , —S(O)—NR 3a R 3b , —S(O) 2 —NR 3a R 3b , —C 1-6 alkyl-CONR 3a R 3b , —C 1-6 alkyl-NR 3a R 3b , —N(R 3a )—COR 3a , —N(R 3a )—CONR 3a R 3b , —C 1-6 alkyl-SONR 3a R 3b , —C 1-6 alkyl-SO 2 NR 3a R 3b , CN, —COR 3a , —O—C 1-6 alkyl; wherein the R 3 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl.
5 . The compound of claim 4 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the R 3 group is selected from the group consisting of: —CONR 3a R 3b , —C 1-6 alkyl-CONR 3a R 3b , —C 1-6 alkyl-NR 3a R 3b , —N(R 3a )—COR 3b , and —N(R 3a )—CONR 3a R 3b , —COR 3a .
6 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the R 3a and R 3b are independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C 0-6 alkyl-C 3-6 cycloalkyl, and 5-6 membered heterocyclyl; or R 3a and R 3b are optionally combined to form a C 3-10 cycloalkyl, a heterocyclyl; wherein the C 1-6 alkyl, the C 1-6 haloalkyl, the —C 2-6 alkenyl, the —C 2-6 alkynyl, the C 0-2 alkyl-C 3-6 cycloalkyl, the 5-6 membered heterocyclyl, the C 3-10 cycloalkyl and the heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 haloalkyl.
7 . The compound of claim 6 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the R 3a and R 3b are independently selected from the group consisting of H, C 1-6 alkyl, and C 1-6 haloalkyl.
8 . The compound of claim 6 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the R 3a and R 3b are optionally combined to form a C 3-10 cycloalkyl, a heterocyclyl, a C 6-10 aryl, and a 5-10 membered heteroaryl; the C 3-10 cycloalkyl, the heterocyclyl, the C 6-10 aryl, or the 5-10 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, —O—C 1-6 alkyl, and C 1-6 haloalkyl.
9 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, the R 3 group is
wherein the Ring D is C 3-10 cycloalkyl or 3-10 membered heterocyclyl; wherein X 4 is N or CH; wherein the Ring D is optionally substituted with oxo, halo, C 1-6 alkyl, —O—C 1-6 alkyl, and C 1-6 haloalkyl; wherein heterocyclyl has one to four heteroatoms, each is independently N, O, or S.
10 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the R 3 group is selected from the group consisting of
11 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Ring C is selected from the group consisting of aryl, 5-6 membered heteroaryl and C 3-10 cycloalkyl.
12 . The compound of claim 11 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Ring C is 5-6 membered heteroaryl.
13 . The compound of claim 11 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Ring C is selected from the group consisting of
14 . The compound of claim 13 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Ring C is
15 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Ring C is C 3-10 cycloalkyl; wherein the cycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl and C 1-6 haloalkyl.
16 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein X 3 is O.
17 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein X 3 is —CR c R d .
18 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R b is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-6 alkyl —C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl, F and OH; wherein two R b groups are optionally combined to form a C 3-10 cycloalkyl or a heterocyclyl; wherein each R b is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl.
19 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R b is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, —C 1-6 alkyl —C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl; wherein two R b groups are optionally combined to form a C 3-10 cycloalkyl or a heterocyclyl; wherein each R b is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl.
20 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R 1 is independently selected from the group consisting of halogen, oxo, —C 1-6 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkoxy, —C 1-6 haloalkyl and —C 3-10 cycloalkyl.
21 . The compound of claim 20 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R 1 is independently selected from the group consisting of halogen, —C 1-6 alkyl, —C 1-6 haloalkyl and —C 3-10 cycloalkyl.
22 . The compound of claim 21 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R 1 is independently selected from the group consisting of —C 1-6 alkyl, —C 1-6 haloalkyl and —C 3-10 cycloalkyl.
23 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R 2 is —C 0-1 alkyl-C 3-9 cycloalkyl; wherein the —C 0-1 alkyl-C 3-9 cycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of C 3-6 cycloalkyl, halo, CH 3 , CHF 2 , CF 3 , OH and oxo.
24 . The compound of claim 23 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R 2 is selected from the group consisting of:
wherein R 2a and R 2b is selected from the group consisting of H, halo, C 1-3 alkyl;
And R 2 is optionally substituted with one or more halo and C 1-6 alkyl.
25 . The compound of claim 24 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R 2 is selected from the group consisting of
26 . The compound of claim 25 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R 2 is selected from the group consisting of
27 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure selected from the group consisting of Formula I-A-1, Formula I-A-2, Formula I-A-3 and I-A-4:
28 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure selected from the group consisting of Formula I-A-5, Formula I-A-6, Formula I-A-7 and Formula I-A-8:
wherein Z 4 is O, S, S═O, S(═O) 2 , or NR b1 ;
wherein X 1 is O, S, or NH; and
wherein Z 1 , Z 2 or Z 3 is independently N or —C—R a .
29 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure selected from the group consisting of Formula I-A-9, Formula I-A-10, Formula I-A-11 and Formula I-A-12:
wherein Z 4 is O, S, S═O, S(═O) 2 , or NR b1 ;
wherein X 1 is O, S, or NH;
wherein Z 1 , Z 2 or Z 3 is independently N or —C—R a ; and
wherein Ring C is aryl, 5-6 membered heteroaryl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, —C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-C 3-10 heterocyclyl, —C 1-6 alkyl-aryl, or —C 1-6 alkyl-5-6 membered heteroaryl; wherein the aryl, the 5-6 membered heteroaryl, the C 3-10 cycloalkyl, the C 3-10 heterocyclyl, the —C 1-6 alkyl-C 3-10 cycloalkyl, the —C 1-6 alkyl-C 3-10 heterocyclyl, the —C 1-6 alkyl-aryl, or the —C 1-6 alkyl-5-6 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 alkoxy.
30 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure of Formula I-A-13:
wherein Z 4 is O, —C(R b1 R b2 )—, —N(R b1 )—;
X 5 is N or CH;
wherein R b1 , R b2 , R b3 and R b4 is independently selected from the group consisting of —C 1-6 alkyl, —C 1-6 haloalkyl, O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CO—C 1-6 alkyl, COOC 1-6 alkyl, —CO—C 1-6 haloalkyl, —CO—NR 3a R 3b , —CH 2 —NR 3a R 3b , —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl, —C 1-6 alkyl-C 6-10 aryl, —C 1-6 alkyl-5-10 membered heteroaryl, H, F, —CH 3 , —CHF 2 , —CF 3 , and OH; and R b3 and R b4 are optionally combined to form a C 3-10 cycloalkyl or a heterocyclyl; wherein the C 3-10 cycloalkyl or heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of oxo, halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl;
wherein the R 3a and R 3b is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C 0-6 alkyl-C 3-6 cycloalkyl, and 5-6 membered heterocyclyl; or R 3a and R 3b are optionally combined to form a C 3-10 cycloalkyl, a heterocyclyl; wherein the C 1-6 alkyl, the C 1-6 haloalkyl, the —C 2-6 alkenyl, the —C 2-6 alkynyl, the CO-2 alkyl-C 3-6 cycloalkyl, the 5-6 membered heterocyclyl, the C 3-10 cycloalkyl and the heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 haloalkyl; and
wherein n a is 0, 1 and 2.
31 . The compound of claim 30 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R b3 and R b4 are independently selected from the group consisting of H, —C 1-6 alkyl, —C 1-6 haloalkyl, 0-C 1-6 alkyl, —O—C 1-6 haloalkyl, —C 3-10 cycloalkyl, heterocyclyl, —C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl; and R b3 and R b4 are optionally combined to form a C 3-10 cycloalkyl or a heterocyclyl; wherein the C 3-10 cycloalkyl or heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl.
32 . The compound of claim 30 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R b4 is selected from the group consisting of —C 1-6 alkyl, —C 1-6 haloalkyl, —C 3-10 cycloalkyl, heterocyclyl, —C 1-6 alkyl-C 3-10 cycloalkyl, and —C 1-6 alkyl-heterocyclyl; wherein the C 3-10 cycloalkyl or heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl.
33 . The compound of claim 30 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R b4 is selected from the group consisting of —C 1-6 alkyl, —C 3-10 cycloalkyl and heterocyclyl; wherein the C 3-10 cycloalkyl or heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl.
34 . The compound of claim 30 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein X 5 is N.
35 . The compound of claim 30 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein X 5 is CH.
36 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure of Formula I-A-18:
37 . The compound of claim 29 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Z 4 is selected from the group consisting of O and CH 2 .
38 . The compound of claim 37 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Z 4 is O.
39 . The compound of claim 37 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein Z 4 is CH 2 .
40 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure of Formula I-A-14:
41 . The compound of claim 40 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein n a is 0 and 1.
42 . The compound of claim 40 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R b4 is selected from the group consisting of —C 1-6 alkyl, —C 1-6 haloalkyl, —C 3-10 cycloalkyl, heterocyclyl, —C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl, H, and F; wherein the C 3-10 cycloalkyl or heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl.
43 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure of Formula I-A-15:
wherein X 5 is selected from the group consisting of O, —N(R x5 )—, —C(R X6 R X7 )—, S, S(O) and S(O) 2 ;
m1 and m2 is 0, 1, 2 and 3;
n a is 0, 1 and 2;
wherein R x5 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, —C 3-10 cycloalkyl, —CO—C 1-6 alkyl and —CO—C 1-6 haloalkyl; and
R x6 and R x7 is independently selected from the group consisting of H, halo, C 1-6 alkyl, and C 1-6 haloalkyl.
44 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure of Formula I-A-16:
wherein n a is 0, 1 and 2.
45 . The compound of claim 44 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein R b4 is selected from the group consisting of —C 1-6 alkyl, —C 1-6 haloalkyl, —C 3-10 cycloalkyl, heterocyclyl, —C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl, H, and F; wherein the C 3-10 cycloalkyl or heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl.
46 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure of Formula I-A-17:
wherein X 5 is O, —N(R x5 )—, —C(R X6 R X7 )—, S, S(O) and S(O) 2 ;
m1 and m2 is 0, 1, 2 and 3;
n a is 0, 1 and 2;
wherein R x5 is H, C 1-6 alkyl, C 1-6 haloalkyl, —CO—C 1-6 alkyl, —C 3-10 cycloalkyl and —CO—C 1-6 haloalkyl; and
R x6 and R x7 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl.
47 . The compound of claim 1 , pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof, wherein the compound has a structure of Formula I-A-19:
48 . A compound of Formula II:
pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof,
wherein Ring C is aryl or 5-6 membered heteroaryl;
wherein Ring C is optionally substituted with one or more R 1 ;
wherein R 1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
wherein R 1 is optionally substituted with halogen, oxo, —OH, —CN, —C 1-6 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkoxy, —C 1-6 haloalkyl, —C 3-10 cycloalkyl, heterocyclyl, —C 6-10 aryl, 5-10 membered heteroaryl;
wherein each of R c and R d is independently selected from the group consisting of H and halo;
wherein n is 0 or 1;
wherein R 2 is selected from the group consisting of —C 0-1 alkyl-C 3-9 cycloalkyl, —C 1-6 alkyl and —C 1-2 alkyl-O—C 1-3 alkyl, wherein the —C 0-1 alkyl-C 3-9 cycloalkyl, the —C 1-6 alkyl or the —C 1-2 alkyl-O—C 1-3 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of C 3-6 cycloalkyl, halo, CH 3 , CHF 2 , CF 3 , OH and oxo;
wherein X 1 is NH, O, or S;
wherein X 2 is N, O, or S; X 2 is optionally attached to an atom in ring A and forms another ring next to Ring A;
wherein Ring A is selected from the group consisting of
wherein each of Z 1 , Z 2 and Z 3 is independently selected from the group consisting of N, N═O, and —C—R a , wherein R a is selected from the group consisting of H, F, Cl, —CH 3 , —CHF 2 , —CF 3 , OH, —OCH 3 and —OCF 3 ;
wherein Ring B, which is fused to ring A, is selected from the group consisting of 4-7 membered heterocycloalkyl, 4-7 membered heterocycloaryl, 4-7 membered cycloalkyl, and 4-7 membered cycloalkenyl, wherein each of the 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloaryl, the 4-7 membered cycloalkyl, and the 4-7 membered cycloalkenyl is optionally saturated and unsaturated bridged-ring;
wherein Ring B is optionally substituted with one or more R b , each of R b is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-6 alkyl —C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl, —C 1-6 alkyl —C 6-10 aryl, —C 1-6 alkyl-5-10 membered heteroaryl, F, —CH 3 , —CHF 2 , —CF 3 , and OH; wherein two R b groups are optionally combined to form a C 3-10 cycloalkyl or a heterocyclyl or a C 6-10 aryl or 5-10 membered heteroaryl; wherein each R b is optionally substituted with one or more halo;
wherein Ring B is substituted with R 3 , wherein R 3 is selected from the group consisting of
wherein each of R 3a and R 3b is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C 0-2 alkyl-C 3-6 cycloalkyl, and 5-6 membered heterocyclyl; wherein R 3a and R 3b are optionally combined to form a C 3-10 cycloalkyl, a heterocyclyl, a C 6-10 aryl, or a 5-10 membered heteroaryl.
49 . A compound of Formula III:
pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof,
wherein Ring C is aryl, 5-6 membered heteroaryl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, R x —C 3-10 cycloalkyl, R x —C 3-10 heterocyclyl, R x -aryl and R x -5-6 membered heteroaryl; wherein R x is halo or —C 1-6 alkyl;
wherein Ring C is optionally substituted with one or more R 1 ;
wherein each R 1 is independently selected from the group consisting of OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CO—C 1-6 alkyl, —CO—C 1-6 haloalkyl, —CO—NR 3a R 3b , C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
wherein each R 1 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, oxo, —OH, —CN, —C 1-6 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkoxy, —C 1-6 haloalkyl, —C 3-10 cycloalkyl, heterocyclyl, —C 6-10 aryl, 5-10 membered heteroaryl, —S(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl and —S—C 1-6 alkyl;
wherein n is 0 or 1;
wherein R 2 is selected from the group consisting of —C 0-1 alkyl-C 3-9 cycloalkyl, —C 1-6 alkyl and —C 1-2 alkyl-O—C 1-3 alkyl, wherein the —C 0-1 alkyl-C 3-9 cycloalkyl, the —C 1-6 alkyl or the —C 1-2 alkyl-O—C 1-3 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of C 3-6 cycloalkyl, halo, CH 3 , CHF 2 , CF 3 , OH and oxo;
wherein X 1 is NH, O, or S;
wherein X 2 is N, O, or S; and wherein X 2 is optionally attached to an atom in Ring A and forms another ring next to Ring A;
wherein X 3 is O or —CR c R d ; and wherein each of R c and R d is independently selected from the group consisting of H, halo and —C 1-6 alkyl;
wherein Ring A is selected from the group consisting of
wherein each of Z 1 , Z 2 and Z 3 is independently selected from the group consisting of —N═, —N(═O)═ and —C(R a )═, wherein R a is selected from the group consisting of H, F, Cl, Br, I, —C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OH, CN, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, aryl and 5-10 membered heteroaryl;
wherein Ring B, which is fused to Ring A, is selected from the group consisting of 4-7 membered heterocycloalkyl, 4-7 membered heterocycloaryl, 4-7 membered cycloalkyl, and 4-7 membered cycloalkenyl, wherein each of the 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloaryl, the 4-7 membered cycloalkyl, and the 4-7 membered cycloalkenyl is optionally saturated or unsaturated bridged-ring;
wherein Ring B is optionally substituted with one or more R b , each of R b is independently selected from the group consisting of CN, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CO—C 1-6 alkyl, COOC 1-6 alkyl, —CO—C 1-6 haloalkyl, —CO—NR 3a R 3b , —CH 2 —NR 3a R 3b , —NR 3a —CO—C 1-6 alkyl, —NR 3a , —COOC 1-6 alkyl, —NR 3a —CO—C 1-6 haloalkyl, —NR 3a —CO—NR 3a R 3b , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-6 alkyl —C 3-10 cycloalkyl, —C 1-6 alkyl-heterocyclyl, —C 1-6 alkyl —C 6-10 aryl, —C 1-6 alkyl-5-10 membered heteroaryl, F, —CH 3 , —CHF 2 , —CF 3 , and OH; wherein two R b groups are optionally combined to form a C 3-10 cycloalkyl or a heterocyclyl or a C 6-10 aryl or 5-10 membered heteroaryl; wherein each R b is optionally substituted with one or more substituents each independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CO—C 1-6 alkyl, COOC 1-6 alkyl, —CO—C 1-6 haloalkyl, —CO—NR 3a R 3b , —CH 2 —NR 3a R 3b , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
wherein Ring B is substituted with R 3 , wherein R 3 is selected from the group consisting of
—CONR 3a R 3b , —S(O)—NR 3a R 3b , —S(O) 2 —NR 3a R 3b , —C 0-6 alkyl-CONR 3a R 3b , —C 0-6 alkyl-NR 3a R 3b , —N(R 3a )—COR 3a , —N(R 3a )—CONR 3a R 3b , —C 0-6 alkyl-SONR 3a R 3b —C 0-6 alkyl-SO 2 NR 3a R 3b , —C(S)—NR 3a R 3b , CN, 5-10 membered heteroaryl, —COR 3a , —P(O)(OR 3a OR 3b ), —S(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, C 1-6 alkyl, —C 1-6 alkyl- C 3-10 cycloalkyl, —O—C 1-6 alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl and alkylcycloalkyl; wherein the 5-10 membered heteroaryl, the —S(O)—C 1-6 alkyl, the —S(O) 2 —C 1-6 alkyl, the C 1-6 alkyl, the —C 1-6 alkyl-C 3-10 cycloalkyl, the —O—C 1-6 alkyl, the aryl, the heterocyclyl, the alkylheterocyclyl, the alkylaryl or the alkylcycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, —O—C 1-6 alkyl and —O—C 1-6 haloalkyl; wherein each of R 3a and R 3b is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C 0-2 alkyl-C 3-6 cycloalkyl, and 5-6 membered heterocyclyl; or R 3a and R 3b are optionally combined to form a C 3-10 cycloalkyl, a heterocyclyl, a C 6-10 aryl, or a 5-10 membered heteroaryl; wherein the C 1-6 alkyl, the C 1-6 haloalkyl, the —C 2-6 alkenyl, the —C 2-6 alkynyl, the C 0-2 alkyl-C 3-6 cycloalkyl, the 5-6 membered heterocyclyl, the C 3-10 cycloalkyl, the heterocyclyl, the C 6-10 aryl, or the 5-10 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 haloalkyl.
50 . A compound having a structure selected from the group consisting of:
pharmaceutically acceptable salts thereof, deuterium substitutes thereof, and isomers thereof.
51 . A pharmaceutical composition, comprising the compound of claim 1 , a pharmaceutically acceptable salt thereof, a deuterium substitute thereof, or an isomer thereof, and a pharmaceutically acceptable excipient.
52 . A method of modulating IL-17A in a subject, comprising:
administering to the subject an effective amount of the compound of claim 1 , a pharmaceutically acceptable salt thereof, a deuterium substitute thereof, or an isomer thereof.
53 . A method of treating an inflammatory disease or condition in a subject, comprising:
administering to the subject an effective amount of the compound of claim 1 , a pharmaceutically acceptable salt thereof, a deuterium substitute thereof, or an isomer thereof.
54 . The method of claim 53 , wherein the inflammatory disease or condition is selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, aspsoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, Palmoplantar Psoriasis, Spondyloarthritis, and Non-infectious Uveitis.Cited by (0)
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